Yoav Yinon

Vascular dysfunction in women with a history of preeclampsia and intrauterine growth restriction: insights into future vascular risk.

Background— Women with a history of placental disease are at increased risk for the future development of vascular disease. It is unknown whether preexisting endothelial dysfunction underlies both the predisposition to placental disease and the later development of vascular disease. The aim of this study was to assess vascular function in postpartum women and to determine whether differences emerged depending on the presentation of placental disease. Methods and Results— Women with a history of early-onset preeclampsia (n=15), late-onset preeclampsia (n=9), intrauterine growth restriction without preeclampsia (n=9), and prior normal pregnancy (n=16) were studied 6 to 24 months postpartum. Flow-mediated vasodilatation and flow-independent (glyceryl trinitrate–induced) vasodilatation were studied through the use of high-resolution vascular ultrasound examination of the brachial artery. Arterial stiffness was assessed by pulse-wave analysis (augmentation index). Laboratory assessment included circulating angiogenic factors (vascular endothelial growth factor, soluble fms-like tyrosine kinase 1, placental growth factor, and soluble endoglin). Flow-mediated vasodilatation was significantly reduced in women with previous early-onset preeclampsia and intrauterine growth restriction compared with women with previous late-onset preeclampsia and control subjects (3.2±2.7% and 2.1±1.2% versus 7.9±3.8% and 9.1±3.5%, respectively; P<0.0001). Flow-independent vasodilatation was similar among all groups. Similarly, the radial augmentation index was significantly increased among women with previous early-onset preeclampsia and intrauterine growth restriction, but not among late preeclamptic women and control subjects (P=0.0105). Circulating angiogenic factors were similar in all groups. Conclusion— Only women with a history of early-onset preeclampsia or intrauterine growth restriction without preeclampsia exhibit impaired vascular function, which might explain their predisposition to placental disease and their higher risk of future vascular disease.

Use of Low Molecular Weight Heparin in Pregnant Women With Mechanical Heart Valves

There are a number of different anticoagulation options for pregnant women with mechanical heart valves. The purpose of this study was to examine maternal thromboembolic complications in women with mechanical valves treated with low-molecular weight heparin (LMWH) throughout pregnancy. This was a substudy of a larger prospective cohort study of pregnant women with heart disease followed from 1998 to 2008. All pregnant women with mechanical left-sided valves who were treated with LMWH throughout pregnancy were included. Maternal thromboembolic events were defined as valve thrombosis, need for valve replacement, or stroke during pregnancy or postpartum (up to 6 months). Twenty-three pregnancies (17 women) occurred in women treated with LMWH and low-dose aspirin: 15 in women with mechanical mitral valves, 9 in women with mechanical aortic valves, and 1 in a woman with both. There was 1 maternal thromboembolic event (4%), which resulted in maternal and fetal death. Five women (22%) developed other adverse cardiac events during pregnancy. Nine pregnancies (43%) had fetal or neonatal adverse events, 5 of which had favorable outcomes. Three pregnancies were complicated by postpartum hemorrhage. In conclusion, carefully monitored LMWH may be a suitable anticoagulation strategy in pregnant women with mechanical heart valves who are unwilling to use warfarin. However, this group of women remains at risk for maternal cardiac and fetal complications. The occurrence of valve thrombosis resulting in maternal death despite therapeutic anti-Xa levels highlights current limitations with anticoagulation in this population.

Pregnancy Outcome After Age 50

OBJECTIVE: To evaluate pregnancy complications occurring after age 50. METHODS: We compared the pregnancy outcomes of women aged 50–64 years with those aged 45–49 years and with the general population. RESULTS: During 5 years from January 1, 1999, to June 30, 2004, 123 women aged 45 years and older gave birth. Fifty-five percent were nulliparous, 24 of 123 were aged 50–64 years, and 99 of 123 women were aged 45–49 years. All women older than age 50 conceived via in vitro fertilization with oocyte donation. For these 123 women, the overall mean gestational age at delivery was 37.6±2.6 weeks. The mean birth weight was 2,684±754 g, significantly lower than the general population, and the incidences of multifetal pregnancies, diabetes, and hypertension were high. Women aged 50 years and older were more likely to be hospitalized during pregnancy than women younger than 50 years (63% versus 22%, P<.001). Neonatal outcome was generally good. Women aged 50 years and older gave birth to significantly more low birth weight babies than those younger than age 50 years (61% versus 32%, P=.002). Gestational age and birth weight were both significantly lower for singletons and multiples in women older than age 50 years compared with those younger than age 50 years (gestational age of singletons 36.9 versus 38.4 weeks, P=.005; birth weight of singletons 2,694 versus 3,027 g, P=.019; gestational age of multiples 35.1 versus 36.4 weeks, P=.01; birth weight of multiples 1,976 versus 2,310 g, P=.038, respectively). CONCLUSION: Pregnant women aged 50–64 years have increased risks of preterm birth, low birth weight babies, diabetes mellitus, hypertension, and hospitalization. LEVEL OF EVIDENCE: II-2

Fetal pleural effusions

The clinical course of primary fetal hydrothorax is unpredictable. Whereas smaller unilateral effusions might remain stable or even regress, this is rarely the case with larger collections. Bilateral effusions, hydrops, preterm delivery and the lack of antenatal therapy are all associated with poor outcome. Once structural and chromosomal anomalies have been excluded, optimal management depends on gestational age, rate of progression, the development of hydrops and associated maternal symptoms. For very large effusions with mediastinal shift, hydrops and/or hydramnios, or when there is rapid enlargement of the effusion, fetal intervention is warranted. Survival can be maximized by pleuroamniotic shunting, which can reverse hydrops and hydramnios and prevent pulmonary hypoplasia. Pleuroamniotic shunting can also be used for the treatment of other large cystic lung lesions, such as a macrocystic congenital cystic adenomatoid malformation or bronchopulmonary sequestration, especially when associated with hydrops.

Fetal thymus size as a predictor of chorioamnionitis in women with preterm premature rupture of membranes.

Emerging evidence indicates that chorioamnionitis is associated with a significant decrease in thymic size at birth in very low birth weight (VLBW) preterm infants. The aim of this study was to determine whether decreased fetal thymus size is associated with histological or clinical chorioamnionitis in patients with preterm premature rupture of membranes (PROM).

Screening, Diagnosis, and Management of Cytomegalovirus Infection in Pregnancy

Congenital cytomegalovirus (CMV) is the most common intrauterine infection and the leading infectious cause of sensorineural hearing loss and mental retardation. This article reviews the issues that relate to the diagnosis and management of this disease, detailing the points that led to the recent published guidelines by the Society of Obstetricians and Gynaecologists of Canada. A MEDLINE/Cochrane search of CMV infection, pregnancy, and prenatal diagnosis found 195 studies between 1980 and 2010. Of these, we examined 59 relevant studies. The probability of intrauterine transmission following primary infection is 30% to 40%, but only 1% after secondary infection. About 10% to 15% of congenitally infected infants will have symptoms at birth, and 20% to 30% of them will die, whereas 5% to 15% of the asymptomatic infected neonates will develop sequelae later. Children with congenital CMV infection following first trimester infection are more likely to have central nervous system sequelae, whereas infection acquired in the third trimester has a high rate of intrauterine transmission but a favorable outcome. The prenatal diagnosis of fetal CMV infection should be based on amniocentesis performed 7 weeks after the presumed time of infection and after 21 weeks of gestation. Sonographic findings often imply poor prognosis, but their absence does not guarantee a normal outcome. The value of quantitative determination of CMV DNA in the amniotic fluid is not yet confirmed. The effectiveness of prenatal therapy for fetal CMV is not yet proven, although CMV-specific hyperimmune globulin may be beneficial. Routine serologic screening of pregnant women or newborns has never been recommended by any public health authority. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this educational activity, the obstetrician/gynecologist should be better able to evaluate the principles of prenatal diagnosis of congenital CMV infection so doctors will be familiar with the tests and procedures needed, in order to reach a diagnosis of congenital CMV; to assess the natural history and outcome of congenital CMV infection enabling obstetricians to counsel prenatally pregnant women with CMV; and to analyze the prognostic markers for fetal CMV, so managing physicians will be able to predict more accurately the outcomes of fetuses infected by CMV.

Cytomegalovirus Infection in Pregnancy

OBJECTIVES To review the principles of prenatal diagnosis of congenital cytomegalovirus (CMV) infection and to describe the outcomes of the affected pregnancies. OUTCOMES Effective management of fetal infection following primary and secondary maternal CMV infection during pregnancy. Neonatal signs include intrauterine growth restriction (IUGR), microcephaly, hepatosplenomegaly, petechiae, jaundice, chorioretinitis, thrombocytopenia and anemia, and long-term sequelae consist of sensorineural hearing loss, mental retardation, delay of psychomotor development, and visual impairment. These guidelines provide a framework for diagnosis and management of suspected CMV infections. EVIDENCE Medline was searched for articles published in English from 1966 to 2009, using appropriate controlled vocabulary (congenital CMV infection) and key words (intrauterine growth restriction, microcephaly). Results were restricted to systematic reviews, randomized controlled trials/controlled clinical trials, and observational studies. Searches were updated on a regular basis and incorporated into the guideline. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. RECOMMENDATIONS The quality of evidence reported in this document has been assessed using the evaluation of evidence criteria in the Report of the Canadian Task Force on Preventive Health Care (Table 1). 1. Diagnosis of primary maternal cytomegalovirus (CMV) infection in pregnancy should be based on de-novo appearance of virus-specific IgG in the serum of a pregnant woman who was previously seronegative, or on detection of specific IgM antibody associated with low IgG avidity. (II-2A) 2. In case of primary maternal infection, parents should be informed about a 30% to 40% risk for intrauterine transmission and fetal infection, and a risk of 20% to 25% for development of sequelae postnatally if the fetus is infected. (II-2A) 3. The prenatal diagnosis of fetal CMV infection should be based on amniocentesis, which should be done at least 7 weeks after presumed time of maternal infection and after 21 weeks of gestation. This interval is important because it takes 5 to 7 weeks following fetal infection and subsequent replication of the virus in the kidney for a detectable quantity of the virus to be secreted to the amniotic fluid. (II-2A) 4. The diagnosis of secondary infection should be based on a significant rise of IgG antibody titre with or without the presence of IgM and high IgG avidity. In cases of proven secondary infection, amniocentesis may be considered, but the risk-benefit ratio is different because of the low transmission rate. (III-C) 5. Following a diagnosis of fetal CMV infection, serial ultrasound examinations should be performed every 2 to 4 weeks to detect sonographic abnormalities, which may aid in determining the prognosis of the fetus, although it is important to be aware that the absence of sonographic findings does not guarantee a normal outcome. (II-2B) 6. Quantitative determination of CMV DNA in the amniotic fluid may assist in predicting the fetal outcome. (II-3B) 7. Routine screening of pregnant women for CMV by serology testing is currently not recommended. (III-B) 8. Serologic testing for CMV may be considered for women who develop influenza-like illness during pregnancy or following detection of sonographic findings suggestive of CMV infection. (III-B) 9. Seronegative health care and child care workers may be offered serologic monitoring during pregnancy. Monitoring may also be considered for seronegative pregnant women who have a young child in day care. (III-B).

Timely and spatially regulated maturation of B and T cell repertoire during human fetal development

Immunocompetence in the developing fetus is temporally and spatially regulated. Developing Immunity The adaptive immune response plays a critical role in protecting the body from both foreign pathogens and internal dangers such as cancer. However, little is known about how the immune system develops during human gestation. Rechavi et al. analyzed differences in B and T lymphocyte ontogeny from 12 to 26 weeks of gestational age. They found that B cell development precedes T cell development and that repertoire maturation is both temporally and spatially regulated. These data can be used as a baseline to improve immune function in developing fetuses and to assess the effects of therapeutic interventions. Insights into the ontogeny of the human fetal adaptive immune system are of great value for understanding immunocompetence of the developing fetus. However, to date, this has remained largely uncharted territory, in large part because blood samples from healthy, early gestation fetuses have been hard to come by. In a comprehensive study, we analyzed levels of T cell receptor excision circles (TRECs), signal-joint κ receptor excision circles (sjKRECs), and intron recombination signal sequence–K-deleting element (iRSS-Kde) rearrangement, and T and B lymphocyte repertoire clonality in human fetuses from 12 to 26 weeks of gestational age. Using next-generation sequencing, we analyzed the diversity and complexity of T cell receptor β (TRB) and immunoglobulin heavy chain (IGH) repertoires in four fetuses at 12, 13, 22, and 26 weeks of gestation and in healthy full-term infants. We report the progressive increase of TREC, sjKREC, and iRSS-Kde levels over time and confirm that B cell development precedes T cell development in the human fetus. Temporally and spatially regulated maturation of B and T cell repertoire diversity and complexity during human fetal development was observed, including evidence that immunoglobulin somatic hypermutation and class switch recombination occur already during intrauterine life. Our results help define physiological levels of immunodeficiency in premature infants and may serve as a reference for future studies aimed at investigating the impact of intrauterine pathologies on fetal immune development and function.

Perinatal outcome following fetal chest shunt insertion for pleural effusion

To evaluate perinatal outcome of fetuses with primary pleural effusions following pleuroamniotic shunting.

Growth restriction as a determinant of outcome in preterm discordant twins.

OBJECTIVE: To estimate the influence of intrauterine growth restriction (IUGR) on the outcome of preterm discordant twins. METHODS: Medical records of preterm twins born at 24–34 weeks of gestation between 1995 and 2000 were reviewed. Significant discordancy was defined as more than 15% difference in birth weight. Small for gestational age (SGA) was defined as birth weight less than 10th percentile, according to a twin-adjusted gestational age nomogram. The smaller twins of 96 discordant twin pairs were evaluated. The SGA-discordant group included the smaller twin of a discordant pair who was also SGA (n = 46); the appropriate-for-gestational-age (AGA)-discordant group included the smaller twin of a discordant pair who was appropriate for gestational age (n = 50). RESULTS: Maternal age, incidence of maternal hypertension, antenatal steroids, and gestational age at delivery were similar between groups. Delivery for suspected fetal compromise complicated significantly more pregnancies in the SGA-discordant group than in the AGA-discordant group (45.6% versus 16%, P = .005), as did respiratory distress syndrome (RDS) (37% versus 8%, P < .05) and intraventricular hemorrhage (21.7% versus 6%, P = .024). Mortality or severe neonatal morbidity (defined as severe RDS, intraventricular hemorrhage grades 3–4, or necrotizing enterocolitis) were significantly higher among neonates in the SGA-discordant group than in the AGA-discordant group (19.5% versus 6%, P = .04). The risk for major morbidity was 7.7-fold greater in the SGA-discordant than in the AGA-discordant group, adjusted for gestational age. CONCLUSION: Growth restriction in preterm discordant twins is associated with a 7.7-fold increased risk for major neonatal morbidity. Therefore, discordant twins with IUGR require closer monitoring than discordant twins without IUGR. LEVEL OF EVIDENCE: II-2